Colorectal cancer (CRC) is a significant cause of cancer morbidity and mortality in the US. Determining who is at higher risk is especially important in CRC because screening tests are available that are proven to reduce death. Risk of CRC development is due to both hereditary and environmental factors which are not uniformly shared between all populations. To date, the field of CRC genetics has focused largely on Caucasian populations, while few studies have included African-American (AA) patients. Determining risk factors in AAs is an especially important goal because both incidence and mortality in this population are not decreasing as they are in all other US populations. At the University of Chicago, we are uniquely equipped to address genetic factors in AAs because we have assembled a large AA CRC case-control series. The main purpose of this study is to identify CRC-susceptibility alleles using a candidate gene screen approach and test for association in AA CRC patients and controls. CRC is particularly amenable to candidate gene studies because biologically relevant pathways have been identified in hereditary CRC syndromes and in the analysis of carcinogenesis in the adenoma to carcinoma sequence. The base excision repair pathway is especially interesting because recent work has elucidated a recessive polyposis syndrome associated with mutations in the gene MYH. Thus, genes involved in this pathway are biologically plausible candidates for harboring CRC-susceptibility alleles, but they have not been adequately identified or characterized in AAs to date. Our hypothesis is that novel susceptibility alleles in base-excision repair genes contribute to risk of CRC development in African-Americans. To test this hypothesis, we will screen candidate base-excision repair genes using high throughput heteroduplex analysis and use sequencing to characterize DNA changes (Specific Aim 1). To control for population stratification in our admixed AA population, we will determine individual ancestry estimates using a set of high informative ancestry informative markers (Specific Aim 2). Finally, we will genotype our putative CRC-susceptibility alleles identified in our candidate gene screens in a series of 400 AA CRC cases and 400 controls and then test for association by logistic regression (Specific Aim 3). With improved understanding of individual risk and proper screening, colorectal cancer is largely a preventable disease. The goal of our study is to better understand hereditary factors that increase risk especially in African-Americans who have the highest incidence and death from this cancer. [unreadable] [unreadable] [unreadable]